Since the FDA approval of cisplatin in 1978, platinum chemotherapy has been the mainstay for a multitude of solid malignancies. The limiting factors of cisplatin's efficacy in a wide variety of cancers has been its systemic toxicity and drug resistance after treatment. The development of second-generation cisplatin drugs, such as FDA approved carboplatin, oxaliplatin, nedaplatin, lobaplatin, and heptaplatin, has addressed some, but not all of the limitations of cisplatin.
A new generation of platinum-based chemotherapy, platinum-acridine hybrid agents, are classical double-stranded DNA intercalators that produce a mono-functional platinum adduct with guanine nucleobases. This mechanism of action, differing from the DNA cross-linking produced by the first and second-generation platinum drugs, has shown increased cytotoxicity and activity in vivo in non-small-cell lung cancer. These drugs are able to elude many of the DNA repair mechanisms by decreasing the structural perturbations that occur upon platination of DNA, as well as have decreased reactivity with sulfur-based nucleophiles, such as glutathione. The overarching issue with platinum-based chemotherapy to date is their inherent, and indiscriminate genotoxicity, resulting in high systemic toxicity.
In an effort to reduce genotoxicity it is important to determine cancer-specific targets and develop platinum-based chemotherapy with decreased non-specific binding to genomic DNA. Classical DNA-targeted drugs employ their cytotoxicity by cross-linking, intercalating, inducing double-strand breaks, groove-binding, and inhibiting or enhancing protein-DNA complexes with genomic double-stranded DNA. New and exciting DNA targets, which could result in decreased systemic toxicity, are DNA secondary structures. These secondary structures, such as G-quadruplexes, triplex DNA, and i-motifs, could provide the key to more selective cancer chemotherapies.
The importance of non-classical DNA secondary structures during transcription has been demonstrated. Negative supercoiling of B-form DNA has been shown to cause local unwinding, which in the case of the c-Myc oncogene promotor, could allow for G-quadruplex or i-motif formation. Due to the limitations of i-motif formation, which involve non-physiological conditions, G-quadruplex formation is a much more valuable target to restricting gene restriction in this promotor region. Similarly, putative G-quadruplex forming regions have been found in the promotor regions of the Bcl-2, c-Kit, RET, VEGF, Hif-1α, PDGFA, c-Myb and KRAS genes, all of which have implications in cancer progression. In addition, putative G-quadruplex forming sequences have been discovered at the telomeric repeat and in the ribosomal DNA (rDNA) found in nucleolar organizer regions (NORs).
Important factors determining specificity to various types of DNA secondary structures are geometry and electrostatic interactions. G-quadruplexes, for instance, have an affinity for drugs containing an extended aromatic moiety, due to their inherent ability to π-π stack with the terminal G-tetrads that make up the G-quadruplex structure. This fact, however, is also true of agents preferring to intercalate Watson-Crick DNA, due to the π-π interactions formed with the hydrogen-bonded bases found in the base-stack. To circumvent this issue with specificity, chemotherapeutic agents must be developed that are too bulky to intercalate the base-stack, such as with 2,7-di-tert-butyl proflavine, therefore shifting its π-π stacking potential to non-classical secondary DNA structures. Derivatives of ethidium bromide, a classical intercalator of Watson-Crick base pairs, suggest that intercalative molecules can be altered to produce G-quadruplex and triplex selectivity. Also, decreasing the positive charge of a drug has been shown to decrease its unwanted interactions with duplex versus G-quadruplex DNA.
One major drawback of platinum-based chemotherapies (including platinum-acridines) is their high level of toxicity when administered systemically. Systemic toxicity is the result of unfavorable pharmacokinetic and pharmacodynamic parameters and off-target reactivity. Dicationic, hydrophilic platinum-acridines, although highly effective against solid tumors, have two major disadvantages: they are excreted from circulation too rapidly through the kidneys (producing high nephrotoxicity) and show indiscriminate reactivity with cellular DNA leading to a high level of non-specific genotoxicity. Both factors most likely contribute to the low tolerability of platinum-acridines as observed in test animals. In an effort to reduce the genotoxicity of a DNA-targeted pharmacophore it is important to determine cancer-specific targets at the nuclear level. Classical DNA-targeted drugs produce their cytotoxicity by cross-linking, intercalating, inducing double-strand breaks, groove-binding, and inhibiting or enhancing protein-DNA complexes with genomic double-stranded DNA.
New and exciting DNA targets, which could result in decreased systemic toxicity, are DNA secondary structures. These secondary structures, such as G-quadruplexes, triplex DNA, and i-motifs, could provide the key to selective cancer chemotherapy. Important factors determining specificity to various types of DNA secondary structures are geometry and electrostatic interactions. G-quadruplexes, a validated cancer target, for instance, have a high affinity for drugs containing an extended aromatic moiety, due to their inherent ability to π-π stack with the terminal G-tetrads that make up the G-quadruplex structure. This fact, however, is also true of agents preferring to intercalate Watson-Crick DNA, due to the π-π interactions formed with the hydrogen-bonded bases found in the base-stack. To circumvent this issue with specificity, chemotherapeutic agents must be developed that are incompatible with classical intercalation into the double-helical base-stack, therefore shifting their π-π stacking potential to non-classical secondary DNA structures.